Promising CR Rates Seen With Bispecific CAR T Cells in Relapsed/Refractory MCL

Nirav N. Shah, MD

A phase 1/2 single-center, prospective trial (NCT04186520) exploring the bispecific anti-CD20/anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (LV20.19) induced a 90-day complete response (CR) rate of 92% in patients with relapsed/refractory mantle cell lymphoma (MCL), according to data presented at the 2023 Transplantation & Cellular Therapy Meetings.¹

Nirav N. Shah, MD, an associate professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, presented results from a phase 1/2 trial where investigators administered CAR T cells at a fixed dose of 2.5 x 106 cells/kg to 14 patients with MCL.

At day 28, the overall response rate (ORR) was 100% with a CR rate of 71%. The minimal residual disease (MRD) negativity rate from days 28 to 65 (n = 12) was 75%.

Twelve patients were evaluable for response at day 90; here, the ORR remained 100%. The 92% CR rate met the prespecified efficacy criteria to continue clinical investigation.

Shah said that, at almost 2 years of follow-up, the median overall survival and progression-free survival have not been reached. Eleven patients have moved onto the phase 2 trial.

“We do believe that these data are suggestive for further investigation. We are developing a multicenter, phase 2 study to really validate these findings beyond our single-center data,” Shah said. “These data hypothesize that the dual targeting of CD20, which is an important target in mantle cell lymphoma outside of CAR T, may be additive in CD19 and improve CAR T-cell therapy outcomes for patients with relapsed/refractory mantle cell lymphoma.”

MCL is an aggressive B-cell malignancy that investigators do not believe is curable using current standard approaches. “It’s a mature B-cell malignancy defined by CD5 positivity and, in particular, BRIGHT CD20 [positivity],” Shah said. “CD20 expression is usually uniform in mantle cell lymphoma.”

In June 2020, The FDA approved the anti-CD19 CAR T-cell agent brexucabtagene autoleucel (brexu-cel; Tecartus) for adults with relapsed/refractory MCL based on data from the ZUMA-2 (NCT02601313) trial.² However, Shah noted that relapse is common following brexu-cel treatment, and the therapy is limited by incidence of grade 3 or higher cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS).

The trial was a phase 1 safety run-in design followed by a single stage 2 design based on the 3-month ibrutinib (Imbruvica) CR rate of 21% achieved in the pivotal PCYC-1104 trial (NCT01236391).³ The target CR rate was 50%. Eligible patients had to have failed 2 lines of therapy or relapsed following autologous or allogeneic transplant.

Investigators used a flexible 8/12 manufacturing platform to develop CAR T cells. In an effort to improve outcomes, Shah and his colleagues shortened manufacturing time by using more potent cytokines for cell expansion to enhance LV20.19 CAR T-cell functionality and persistence. A lymphodepletion regimen administered prior to LV20.19 infusion was comprised of fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m² on days -4, -3, and -2.

The median patient age was 63 years (range, 50-74) and 93% of the cohort was male. Forty-three percent of patients received prior autologous hematopoietic cell transplant (HCT); 14% underwent allogeneic HCT. Ninety-three percent were exposed to BTK inhibitors and 79% had progressed on BTK agents. Shah added that 5 (36%) progressed on a noncovalent BTK inhibitor.

Patients received a median of 5 (range, 2-8) prior lines of therapy. Eleven (79%) previously received bendamustine, but only 2 (14%) received it within 1 year of CAR T-cell therapy. Three patients had p53 deletion and 3 had p53 somatic mutation.

Three patients received the 12-day product vs 11 who received the 8-day product. Manufacturing was deemed successful in 100% of patients. Two patients received the cryopreserved product; 1 had a fungal sinus infection and 1 had rapidly progressive disease who received rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (R-CHOP) following apheresis.

Thirteen (93%) patients experienced grade 1/2 CRS, but there was no incidence of grade 3/4 CRS. Two (14%) patients experienced grade 3/4 ICANS and 1 experienced it at grade 1/2. ICANS resolved following treatment with intrathecal steroids or chemotherapy. Three (21%) patients experienced hemophagocytic lymphohistiocytosis-like toxicities.

Investigators observed 1 nonrelapse mortality at day 46 due to gram-negative rod sepsis. That patient relapsed following allogenic transplant.

“We have seen now durable remissions with immediate follow-up of 22 months and only 1 relapse at the 2-year mark post infusion,” Shah said. Most importantly, from a safety standpoint, we have had no episodes of grade 3 or higher CRS. We had 2 grade 3 ICANS, but 1 of those is confounded by the fact that the patient had mantle cell [lymphoma] in the cerebrospinal fluid. There were no patient recorded ICU hospitalizations.”

Editor’s Note: Dr Shah reported advisory roles with Legend, Epizyme, TG Therapeutics, Kite Pharma, Novartis, LOXO-Lilly Oncology, Janssen, BMS-Juno, Seagen; researcher roles with Miltenyi Biotec and LOXO-Lilly Oncology; consultant roles with Miltenyi Biotec, Lilly Oncology, and Incyte; and a member/founder role with Tundra Therapeutics.

References

Shah NN, Furqan F, Szabo A, et al. Results from a phase 1/2 study of tandem, bispecific anti-CD20/anti-CD19 (LV20.19) CAR T-cells for mantle cell lymphoma. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL.

FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. News release. July 27, 2020. Accessed February 16, 2023. https://www.fda.gov

Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. doi: 10.1056/NEJMoa1306220